The mechanisms of resistance to antidepressant drugs is a key and still unresolved problem of psychopharmacology. Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) play a key role in the ...therapeutic effect of many antidepressants. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT synthesis in the brain. We used zebrafish (
) as a promising model organism in order to elucidate the effect of TPH2 deficiency caused by p-chlorophenylalanine (pCPA) on the alterations in behavior and expression of 5-HT-related (
,
,
,
,
) and BDNF-related (
,
,
,
) genes in the brain after prolonged treatment with two antidepressants, inhibitors of 5-HT reuptake (fluoxetine) and oxidation (pargyline). In one experiment, zebrafish were treated for 72 h with 0.2 mg/L fluoxetine, 2 mg/L pCPA, or the drugs combination. In another experiment, zebrafish were treated for 72 h with 0.5 mg/L pargyline, 2 mg/L pCPA, or the drugs combination. Behavior was studied in the novel tank diving test, mRNA levels were assayed by qPCR, 5-HT and its metabolite concentrations were measured by HPLC. The effects of interaction between pCPA and the drugs on zebrafish behavior were observed: pCPA attenuated "surface dwelling" induced by the drugs. Fluoxetine decreased mRNA levels of
and
genes, while pargyline decreased mRNA levels of
and
genes. Pargyline reduced
,
and
genes mRNA concentration only in the zebrafish treated with pCPA. The results show that the disruption of the TPH2 function can cause a refractory to antidepressant treatment.
: Tryptophan hydroxylase 2 (TPH2) is the key, rate-limiting enzyme of serotonin (5-HT) synthesis in the brain. Some polymorphic variants of the human
gene are associated with psychiatric disorders.
: ...This review focuses on the mechanisms underlying the association between the TPH2 activity and behavioral disturbances in models of psychiatric disorders. Specifically, it discusses: 1) genetic and posttranslational mechanisms defining the TPH2 activity, 2) behavioral effects of knockout and loss-of-function mutations in the mouse
gene, 3) pharmacological inhibition and the activation of the TPH2 activity and 4) alterations in the brain TPH2 activity in animal models of psychiatric disorders. We show the dual role of the TPH2 activity: both deficit and excess of the TPH2 activity cause significant behavioral disturbances in animal models of depression, anxiety, aggression, obsessive-compulsive disorders, schizophrenia, and catalepsy.
: Pharmacological chaperones correcting the structure of the TPH2 molecule are promising tools for treatment of some hereditary psychiatric disorders caused by loss-of-function mutations in the human
gene; while some stress-induced affective disorders, associated with the elevated TPH2 activity, may be effectively treated by TPH2 inhibitors. This dual role of TPH2 should be taken into consideration during therapy of psychiatric disorders.
The
(brain-derived neurotrophic factor) gene contains eight regulatory exons (I-VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. ...The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the
exons I-IX's expressions and serotonin receptors' mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors' and
exons' transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the
exons' expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT
receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of
regulatory exons and the 5-HT
receptor was shown, as was an association between
regulatory exons and fear-induced aggression involving genetic predisposition.
The brain melanocortin system regulates numerous physiological functions and kinds of behavior. The agouti protein inhibits melanocortin receptors in melanocytes. The
(A
) mutation puts the
gene ...under the control of the
gene promotor and causes the agouti protein expression in the brain. In the present article, we investigated the effects of the A
mutation on brain mRNA levels of
,
, and melanocortin-related genes such as
, and their relationship to behavior.
The experiment was performed on 6-month-old males and females of A
/a and a/a (control) mice. Anxiety and obsessive-compulsive behavior were studied in elevated plus-maze and marble- burying tests. The mRNA levels were quantified by qPCR.
A
mutation caused anxiety in males and obsessive-compulsive behavior in females. Positive correlation between
and
genes mRNA levels were shown in the hypothalamus, hippocampus, and frontal cortex in A
/a mice. Reduced RNA concentrations of
and
genes were found respectively in the hypothalamus and frontal cortex in A
/a males. The
gene expression positively correlates with mRNA concentrations of the
gene in the hypothalamus and the
gene in the hypothalamus and frontal cortex.
Possible association of obsessive-compulsive behavior with reduced
,
or
gene expression is suggested.
Kaiso is a bimodal transcriptional repressor. It binds methylated CpG islands or the sequence- specific consensus in the DNA molecule with the Kaiso zinc-finger domain and recruits repressive protein ...complexes to these DNA fragments by the interaction of the BTB/POZ domain with the complex of NCoR1 corepressor and histone deacetylase, thereby performing transcription repression. Kaiso is involved in epigenetic regulation of transcription. Moreover, the complex Kaiso and catenin p120ctn modulates the transcription of the Wnt-target genes. The review discusses the role of Kaiso in the central nervous system. Kaiso molecules are abundant in the brain. MRI study did not show any alterations in the whole brain, hippocampus and striatum in Kaiso null mice. However, in Kaiso deficient mice the lateral ventricles were three-fold smaller compared with wild-type control. Kaiso deficiency increased the locomotor and exploratory activities as well as the prepuls inhibition of acoustic startle reflex without any adverse effect on anxiety-related behavior, learning and memory. At the same time, Kaiso deficiency produces a marked antidepressant-like effect. Thus, Kaiso involved in the mechanism of locomotion and depressive-like behavior. Kaiso inhibitors are expected to be promising atypical antidepressant drugs.
Short-lived turquoise killifish (
) have become a popular model organism for neuroscience. In the present paper we study for the first time their behavior in the novel tank diving test and the levels ...of mRNA of various 5-HT-related genes in brains of 2-, 4- and 6-month-old males and females of
. The marked effect of age on body mass, locomotor activity and the mRNA level of
,
,
,
,
,
,
,
,
,
genes in the brains of
males was shown. Locomotor activity and expression of the Mao gene increased, while expression of
,
,
,
,
,
,
,
,
genes decreased in 6-month-old killifish. Significant effects of sex on body mass as well as on mRNA level of
,
,
,
,
,
,
,
,
, and
genes were revealed: in general both the body mass and the expression of these genes were higher in males.
is a suitable model with which to study the fundamental problems of age-related alterations in various mRNA levels related with the brains 5-HT system.
Tumor necrosis factor alpha (TNF-α) is a cytokine that is responsible for many processes associated with immune response and inflammation. It is involved in the development of an antiviral response ...to many virus infections. This factor was shown to be activated in influenza A virus infection, which enhances production of other cytokines. The overexpression of these cytokines can lead to a cytokine storm. To study the role of TNF-α in the development of pathologies associated with viral infection, we generated a
knockout mouse strain. We demonstrated that these mice were characterized by a significant increase in the number of viral genomes compared to that in the parental strain, but the amount of live virus did not differ. A histopathology of the lungs in the genetically modified animals was significantly lower in terms of interalveolar septal infiltration. The generated model may be used to further study pathological processes in viral infections.
Tyrosine phosphatase STEP (striatal-enriched tyrosine protein phosphatase) is a brain-specific protein phosphatase and is involved in the pathogenesis of many neurodegenerative diseases. Here, we ...examined the impact of STEP on the development of age-related macular degeneration (AMD)-like pathology in senescence-accelerated OXYS rats. Using OXYS and Wistar rats (control), we for the first time demonstrated age-dependent changes in
mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the retina. The increases in STEP protein levels and the decrease of total and STEP phosphatase activities in the retina (as compared with Wistar rats) preceded the manifestation of clinical signs of AMD in OXYS rats (age 20 days). There were no differences in these retinal parameters between 13-month-old Wistar rats and OXYS rats with pronounced signs of AMD. Inhibition of STEP with TC-2153 during progressive AMD-like retinopathy (from 9 to 13 months of age) reduced the thickness of the retinal inner nuclear layer, as evidenced by a decreased amount of parvalbumin-positive amacrine neurons. Prolonged treatment with TC-2153 had no effect on
mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the OXYS retina. Thus, TC-2153 may negatively affect the retina through mechanisms unrelated to STEP.
The mechanisms of autism are of extreme interest due to the high prevalence of this disorder in the human population. In this regard, special attention is given to the transcription factor Freud-1 ...(encoded by the
Cc2d1a
gene), which regulates numerous intracellular signaling pathways and acts as a silencer for 5-HT
1A
serotonin and D2 dopamine receptors. Disruption of the Freud-1 functions leads to the development of various psychopathologies. In this study, we found an increase in the expression of the
Cc2d1a
/Freud-1 gene in the hippocampus of BTBR mice (model of autistic-like behavior) in comparison with C57Bl/6J mice and examined how restoration of the
Cc2d1a
/Freud-1 expression in the hippocampus of BTBR mice affects their behavior, expression of 5-HT
1A
serotonin and D2 dopamine receptors, and CREB and NF-κB intracellular signaling pathways in these animals. Five weeks after administration of the adeno-associated viral vector (AAV) carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a small hairpin RNA (shRNA) that suppressed expression of the
Cc2d1a
/Freud-1 gene, we observed an elevation in the anxiety levels, as well as the increase in the escape latency and path length to the platform in the Morris water maze test, which was probably associated with a strengthening of the active stress avoidance strategy. However, the
Cc2d1a
/Freud-1 knockdown did not affect the spatial memory and phosphorylation of the CREB transcription factor, although such effect was found in C57Bl/6J mice in our previous study. These results suggest the impairments in the CREB-dependent effector pathway in BTBR mice, which may play an important role in the development of the autistic-like phenotype. The knockdown of
Cc2d1a
/Freud-1 in the hippocampus of BTBR mice did not affect expression of the 5-HT
1A
serotonin and D2 dopamine receptors and key NF-κB signaling genes (
Nfkb1
and
Rela
). Our data suggest that the transcription factor Freud-1 plays a significant role in the pathogenesis of anxiety and active stress avoidance in autism.
•C1473G polymorphism in Tph2 gene regulates enzyme activity in mouse brain.•The stress-induced c-Fos mRNA rise is more intensive in the brain of B6-1473G mice.•The polymorphism modifies the effect of ...stress on 5-HT metabolism in the hypothalamus.
Neurotransmitter serotonin (5-HT) is involved in the regulation of stress response. Tryptophan hydroxylase-2 (TPH2) is the key enzyme of serotonin (5-HT) synthesis in the brain. C1473G polymorphism in Tph2 gene is the main factor defining the enzyme activity in the brain of laboratory mice. The effect of interaction between C1473G polymorphism and 30min restriction stress on the behavior in the open field test, c-Fos gene expression and 5-HT metabolism in the brain in adult male of B6-1473C and B6-1473G congenic mouse lines with high and low TPH2 activity was investigated. A significant effect of genotype x stress interaction on c-Fos mRNA in the hypothalamus (F1,21=10.66, p<0.001) and midbrain (F1,21=9.18, p<0.01) was observed. The stress-induced rise of c-Fos mRNA in these structures is more intensive in B6-1473G than in B6-1473C mice. A marked effect of genotype x stress interaction on 5-HT level in the cortex (F1,18=9.38, p<0.01) and 5-HIAA/5-HT turnover rate in the hypothalamus (F1,18=9.01, p<0.01) was revealed. The restriction significantly decreased 5-HT level in the cortex (p<0.01) and increased 5-HIAA/5-HT rate (p<0.001) in the hypothalamus in B6-1473C mice, but not in B6-1473G mice. The present result is the first experimental evidence that C1473G polymorphism is involved in the regulation of the reaction to emotional stress in mice.
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